5Z2C | pdb_00005z2c

Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose.

(2018) Nature 561: 122-126

• PubMed: 30111836 Search on PubMed
• DOI: https://doi.org/10.1038/s41586-018-0433-3
• Primary Citation of Related Structures:  
  5Z2C


• PubMed Abstract: 
  

  Immune recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors often activates proinflammatory NF-κB signalling ¹ . Recent studies indicate that the bacterial metabolite D-glycero-β-D-manno-heptose 1,7-bisphosphate (HBP) can activate NF-κB signalling in host cytosol ^2-4 , but it is unclear whether HBP is a genuine PAMP and the cognate pattern recognition receptor has not been identified. Here we combined a transposon screen in Yersinia pseudotuberculosis with biochemical analyses and identified ADP-β-D-manno-heptose (ADP-Hep), which mediates type III secretion system-dependent NF-κB activation and cytokine expression. ADP-Hep, but not other heptose metabolites, could enter host cytosol to activate NF-κB. A CRISPR-Cas9 screen showed that activation of NF-κB by ADP-Hep involves an ALPK1 (alpha-kinase 1)-TIFA (TRAF-interacting protein with forkhead-associated domain) axis. ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. The crystal structure of the N-terminal domain of ALPK1 and ADP-Hep in complex revealed the atomic mechanism of this ligand-receptor recognition process. HBP was transformed by host adenylyltransferases into ADP-heptose 7-P, which could activate ALPK1 to a lesser extent than ADP-Hep. ADP-Hep (but not HBP) alone or during bacterial infection induced Alpk1-dependent inflammation in mice. Our findings identify ALPK1 and ADP-Hep as a pattern recognition receptor and an effective immunomodulator, respectively.

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Organizational Affiliation: 

National Institute of Biological Sciences, Beijing, China.